Regardless of CNS Involvement, Patients with B-ALL Benefit From Brexu-Cel

Brexucabtagene autoleucel (brexu-cel; Tecartus) demonstrates efficacy and manageable safety in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), even in patients with central nervous system (CNS) involvement—a population historically excluded from clinical trials, according to a new multi-institutional study published in Blood Advances.¹

Toxicity profiles of brexu-cel was comparable between patients with (n = 31) and without (n = 158) CNS involvement. Muhsen IN et al reported that brexu-cel is efficacious in patients with CNS B-ALL, resulting in high rates of CNS disease remission and progression-free and overall survival comparable with those of patients without CNS involvement.

In the CNS group, 74.2% developed cytokine release syndrome (CRS), with only one case of grade 3/4 severity, while 64.5% experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including 11 patients with grade 3/4. These rates mirrored the non-CNS cohort (n=158), in which 84.8% had CRS (12.0% were grade 3/4) and 54.4% had ICANS (30% were grade 3/4). No statistically significant differences were observed in toxicity severity between groups.

Muhsen IN et al reported that most of the patients in the study developed chimeric antigen receptor (CAR) T-cell-related adverse events, including CRS and ICANS, which occurred at similar rates in patients with and without CNS involvement. This is consistent with previous studies reporting a high rate of CRS and ICANS after brexu-cel. For example, 89% of patients enrolled in ZUMA-3 (NCT02614066) had CRS and 60% had neurotoxicity, with about 25% of patients developing grade 3/4 CRS or ICANS.² The trial was an open-label single-arm phase 2 trial demonstrating a 71% complete remission (CR) rate in patients with R/R B-ALL.

Study Details

Data from the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) consortium were evaluated and were collected from 31 US-based academic and community cellular therapy centers.

A total of 189 patients were infused with brexu-cel. In patients with CNS involvement, 15 had CNS-2 disease, defined as the presence of blasts in cerebrospinal fluid with 5 or fewer white blood cells (WBCs) per μL, and 16 had CNS-3 disease, defined as the presence of blasts with 5 or more WBCs per μL and/or clinical signs/symptoms.

Investigators reported that a total of 17 patients (54.8%) had CNS disease without morphological medullary disease. Among these patients, 11 had minimal residual disease (MRD)-positive or unknown CR, and 6 had MRD-negative CR. The other 14 patients had both morphological medullary and CNS disease at preapheresis assessment.

In the cohort with CNS involvement, the median age was 46.5 years (range, 24-76), and 58.1% were male. More patients had Ph-positive disease (45.2%) than Ph-negative disease (35.5%). Four patients had molecular mutations and included TP53, SLC16A3-NOTCH1, TP53/DNMT3A, and PPM1D/CDKN2A/MLL3.

The median age in patients with no CNS involvement was 46 years (range, 18-81), most were male (56.3%), and most had Ph-negative disease (54.4%).

The median follow-up was 13.8 months for the entire cohort. In the CNS group, 12 patients had R/R disease after brexu-cel, with a median time to relapse of 100 days. Of 12 relapses, 5 occurred in the CNS with or without systemic disease. The remaining relapses occurred in the BM (n = 2), were extramedullary (n = 1), or had no specified site of relapse documented (n = 4). The cumulative incidence of relapse at 1 year was 39% in the CNS group compared with 35% in patients without CNS disease (P =.54).

Survival and Relapse Data

The median follow-up was 13.8 months for the entire cohort. In the CNS group, 12 patients had R/R disease after brexu-cel, with a median time to relapse of 100 days. Of 12 relapses, 5 occurred in the CNS with or without systemic disease. The remaining relapses occurred in the bone marrow (n = 2), were extramedullary (n = 1), or had no specified site of relapse documented (n = 4). The cumulative incidence of relapse at 1 year was 39% in the CNS group compared with 35% in patients without CNS disease (P =.54).

A total of 8 patients (25.8%) in the CNS group and 56 patients (35.4%) in the non-CNS group died. In the CNS group, 4 of 8 patients died in the absence of leukemia relapse; 2 died because of CRS and ICANS, and 2 died because of infections and multiorgan failure. The 6- and 12-months PFS in the CNS group were 57% (95% CI, 38%-73%) and 47% (95% CI, 29%-34%), respectively. The median PFS was 263 days.

There was no statistically significant difference in PFS between the CNS and non-CNS groups (P =.83). The 6- and 12-month OS in the CNS group were 84% (95% CI, 65%-93%) and 76% (95% CI, 57%-88%), respectively. The median OS was not reached. There was no statistically significant difference in OS between the CNS and non-CNS groups (P =.14).

The investigators wrote that their findings were promising and suggest the benefit of including patients with CNS B-ALL in future CAR T-cell clinical trials while underscoring the ongoing work needed to optimize efficacy and reduce toxicity.

REFERENCES:

1. Muhsen IN, Roloff GW, Faramand R, et al. Outcomes of brexucabtagene autoleucel in patients with relapsed/refractory acute lymphoblastic leukemia with CNS involvement. Blood Adv. 2025;9(16):4081–4089. doi:10.1182/bloodadvances.2024015779

2. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8